Implications of Pharmacogenomics in the Current and Future Treatment of Asthma

BACKGROUND: For more than a generation, managed care has attempted to eliminate variation in care delivery in the hope of producing predictable outcomes. But the population-based, guideline-driven approach may not have fully appreciated the importance of individual behavior (adherence) and environment, as well as individual genetic makeup. Genetic variation in response to currently recommend ed therapies may require tailoring medication regimens to the individual patient to achieve optimal outcomes. OBJECTIVES: To review the pharmacogenomics of asthma and how they impact the medications utilized for its treatment. METHODS: A search of PubMed that included the time period from January 1991 through September 2005 and the key terms: asthma pharmacogenetics, asthma genetics, asthma response variability, asthma glucocorticoid resistance, asthma steroid-unresponsive, asthma control, beta-agonist genomics, beta 2-receptor abnormalities, asthma genotypes, and leukotriene inhibitor polymorphisms produced 105 articles. Forty-five were rejected for this subject review by failing the following criteria: (1) results in humans, not animals, (2) provide information about clinical implications as well as description of molecular and cellular mechanism of action or the site of action on the gene, and (3) preference for manuscripts that quantified information/results over those that just stated that there were observed differences. The remaining 60 references were reviewed, and 7 references were added after peer review. RESULTS: There are now limited examples of gene polymorphisms that can influence responses to beta 2-agonists, glucocorticosteroids, and leukotriene modifiers in patients with asthma. Gene mutations that are known to alter the response to asthma therapy include Arg/Arg atr position 16, mutations of LTC4S, ALOX5, and GR/NR3C1, increased expression of GR , CRHR1 variants, and mutations in CYP1A2 (-22964 [G/A]), and T 314 allele for histamine N-methyltransferase. Some of the effects associated with these mutations are increased/decreased response to therapy, glucocorticoid resistance, decreased theophylline clearance and possible toxicity, and increased bronchoconstriction. CONCLUSIONS: Understanding the impact of genetic variations on response to therapy may ultimately improve treatment outcomes for patients with asthma. However, despite substantial progress, no individual gene polymorphisms have been associated with altered responses to asthma treatment in large numbers of patients. It is not yet possible to tailor medication therapy for asthma based on genetic characteristics of individual patients.

C linical practice has evolved from anecdotal case reports, to collections of signs and symptoms, to evidencebased medicine. This approach has generally embraced population-based approaches to caret op roduce am ore consistent outcome from different providers. Treatment of both acute and chronic disease is now driven by guidelines based on results from large-scale, well-controlled clinical trials. Examples of well-known guidelines include those for treatment of hypertension, dyslipidemia, diabetes, and depression. [1][2][3][4] In general, treatment guidelines centralize information about phenotypic characteristics (e.g., sex, age, and body weight), patient and family history, and disease severity (e.g., blood pressureand cholesterol level) to drive treatment decisions in a standardized manner. 1,2 This has led to adramatic improvement in overall carea si th as diminished the variability of individual practitioners in their application of evidence.
The sequencing of the human genome was af undamentally important step in the evolution of medicine and aq uantum leap in our understanding of genes, their association with specific diseases, and new targets of pharmacotherapy.Since the completion of the draft of the human genome in early 2001, genebased therapies have begun to influence patient care. Advances in the management of hepatitis C, 5 schizophrenia, 6 leukemia, 7 prostate cancer, 8 lung cancer, 9 and breast cancer 10 have all resulted from increased understanding of the genes associated with these diseases. Understanding the manner in which agiven patient' sg enetic inheritance may influence response to therapy has increased attention on individualization of therapy based on such information. 10 The highly complex respiratorys ystem is an important pathway for the entryo fd isease-causing vectors, including viruses, bacteria, fungi, toxins, and antigens. 11 Interpatient variability in response to treatments for respiratorydiseases, such as asthma, is veryh igh, 12,13 but efforts to understand potential genetic sources of this variability have lagged behind those for other conditions. The objective of this review is to highlight the pharmacogenomics of asthma and how they impact the medications utilized to treat this disease.

■■ Overview of Asthma Pathophysiology
Asthma is ac hronic inflammatoryd isease of the airways that is characterized by intermittent and at least partially reversible bronchoconstriction, as well as by airway hyperresponsiveness to awide variety of stimuli. 13 The inflammatory features characteristic of asthma include infiltration of the airways by inflammatoryc ells that release various cytokines and inflammatorym ediators. These mediators result in an increase in airway edema and mucus secretion, hypertrophy and hyperplasia of airway smooth muscle, and increased airway vascularity,a ll of which contribute to airflow obstruction. 13,14 Therei sw ide variability in the pathophysiologic features apparent in different patients with asthma. In many patients, eosinophils aret he predominant inflammatoryc ell type, while in others, neutrophils rather than eosinophils have been shown to be present as the dominant inflammatorycell. 15 Variability in response to medications is also commonly seen in asthmatics. 3 Therea re many potential reasons for this variability.A sn oted above, asthma is typically characterized by eosinophil activation and infiltration of the airways, but some patients have increased neutrophils and lack eosinophils in their airways. 13 Such patients may have decreased responses to leukotriene response modifiers and/or inhaled corticosteroids.

Epidemiology
Asthma is averycommon disease associated with high morbidity. Review of worldwide data indicates that the prevalence of asthma has increased substantially over the last 20 years, but the reasons for this aren ot clear. 16 Results from the United States indicate that the prevalence of asthma had increased by 75% from 1980 to 1994 17 and asthma now affects 8% to 10% of the U.S. population. 18 In as urvey of moret han 42,000 U.S. households, 30% of patients with mild to moderate disease and 70% of those with moderate to severed isease, based on symptoms, reported some level of functional impairment. 19 In 1998, the direct and indirect costs associated with medical care of patients with asthma exceeded $11 billion ($7.5 billion and $3.8 billion, respectively). 20 ■■ Asthma Diagnosis, Therapy,and Current Treatment Guidelines Diagnosis Accurate diagnosis is the critical component in the management of asthma. Generally,a sthma presents episodic symptoms of airflow obstruction that area tl east partially reversible and not attributable to other pathologies. Chronic obstructive pulmonarydisease, vocal corddysfunction in adults, and cystic fibrosis and aspiration in children, must be ruled out in the differential diagnosis of asthma. Spirometric studies utilizing prebronchodilator and postbronchodilator therapy measuring forced expiratoryv olume in 1s econd (FEV 1 )a nd peak flow arev aluable in measuring reversibility and classifying disease severity. 21 Allergens and irritants that can trigger symptoms or exacerbations should be identified and removed or exposurel imited. 21 Thus, while certain features arec onsidered characteristic of asthma, heterogeneity exists in terms of pathologic presentation and response to therapy.Itseems logical that genetic variability may explain some of this heterogeneity.

Current Treatment Guidelines and Treatment Efficacy
The National Asthma Education and Prevention Program guidelines recommend as tepwise approach to pharmacologic therapy,w hereby the amount and frequency of medications ared ictated by the severity of the asthma and directed toward suppression of increasing airway inflammation. According to these guidelines, therapy is initiated aggressively to establish prompt control and then slowly stepped-down to minimize the risk of adverse events without sacrificing efficacy. 21 Achievement of treatment goals areless than optimal in many patients. 25,26 For some this may be due to poor adherence to treatment guidelines, but for asmall subgroup, this may be due, in part, to genetic polymorphisms as well as the fact that disease severity may be misclassified in some patients with asthma, resulting in inappropriate therapy. 27,28 Even treatment that is fully consistent with current guidelines fails to control asthma in some patients. Results of arandomized, stratified, double-blind, parallel-group study of 3,421 patients with uncontrolled asthma showed that fully optimized, long-term drug therapy with inhaled corticosteroids or inhaled corticosteroids plus al ongacting beta-agonist controlled approximately 75% of this group. While these results suggest that the majority of patients could reach guideline-defined measures of control, approximately 25% of these managed patients could not achieve control as defined by the Global Initiative for Asthma and the National Institutes of Health. 29 These results suggest that other factors, Implications of Pharmacogenomics in the Current and Future Treatment of Asthma such as severity of disease, concurrent illness, environmental exposures, medication noncompliance, and interpatient genetic variability in response to asthma therapy may play important roles in treatment efficacy.Itisreasonable to suggest that current treatment guidelines for asthma therapy should be reviewed in light of the latest information about genetic determinants of responsivity to commonly used asthma therapies.
■■ Genetic Determinants of Responsitivity to Asthma Therapy Genetic factors, including polymorphism in agene or arandom DNA position (single nucleotide polymorphism [SNP]), or in as eries of associated alleles, play ar ole in determining heterogeneous responses to pharmacological treatment among patients with asthma. Drug therapy tailored to an asthmatic patient' sg enotype may result in ac linically important increase in efficacy and areduction in adverse events. 30

Specific Genetic Mutations That Alter Responses to Different Asthma Therapies
Gene mutations that alter responses to asthma therapy are summarized in Table 1and described in detail in the following sections.

Beta 2-Agonists
Beta 2-agonists arei mportant bronchodilator drugs commonly used in the treatment of asthma. The beta 2-adrenoreceptor gene is expressed in bronchial smooth muscle cells and induces dilation in response to endogenous catecholamine or exogenous triggers. Several polymorphisms have been described in this gene, which is located on the chromosome 5q31-32. Three coding polymorphisms, located at positions 16, 27, and 164, have been studied. 30 Clinical studies have indicated that the Arg/Argg enotype for residue 16 of the beta 2-receptor alters responses to treatment and disease severity in patients with asthma. Results from one study showed that albuterol-evoked FEV 1 was higher and the response was morerapid in Arg16 homozygotes compared with carriers of the Gly16 variant (18% increase versus 4.9% increase, P <0.03). 31 Similarly,spirometric assessment of 269 participants in alongitudinal study of asthma indicated that homozygotes for Arg16 were5 .3 times morel ikely than Gly16 homozygotes to respond (>15.3% increase in FEV 1 )t oc hallenge with 180 mcg albuterol. 32 In contrast, clinical trial results have indicated ad ecreased response to longer-term beta 2-agonist treatment among patients with Arg/Argg enotype for residue 16 of the beta 2-receptor as well as increased risk of exacerbations among patients with this genotype who weretreated with ashort-acting beta 2-agonist. 33,34 The Beta-Adrenergic Response by Genotype trial was designed to establish ag enotype-dependent effect of albuterol use on airway function. Patients with mild asthma wereenrolled based on clinical criteria and their genotype (Arg/Argo rh omozygous for glycine [Gly/Gly]) at the locus encoding the 16th amino acid in the beta 2-adrenocepter. 33 Results showed that patients with the Arg/Argg enotype had increased peak expiratoryfl ow rates (PEFR) when beta 2-agonists werewithdrawn as arescue inhaler and replaced with ipratropium bromide. In contrast, patients with the Gly/Gly genotype showed good responses to beta 2-agonist therapy,that reversed when it was withdrawn. During randomized treatment, patients with the Gly/Gly genotype had an increase in morning PEFR of 14 L/min versus placebo with regularly scheduled albuterol. Patients with the Arg/Arg genotype had lower morning PEFR (-10 L/min) during treatment with albuterol than during the placebo period, when albuterol use was limited. The genotype-attributable treatment difference was thus -24 L/min. 33 This information indicates that chronic treatment with ashort-acting beta 2-agonist should probably be avoided in asthma patients with the Arg/Argg enotype. 33 It is estimated that 15% (16% of whites and 20% of blacks) of the population is homozygous for Arg16. 35,43 Ar etrospective analysis of relationships between polymorphisms at codons 16 and 27 of the beta 2-adrenoceptor and clinical outcomes in arandomized, placebo-controlled, crossover trial of regularly scheduled salbutamol and salmeterol in 115 patients with mild to moderate asthma indicated that patients with the Arg/Argg enotype had moref requent exacerbations during salbutamol treatment than with placebo (1.91 versus 0.81, P =0 .005). 34 No significant treatment-related differences occurred for heterozygous Arg-Gly patients or homozygous Gly-16 patients. 34

Leukotriene Response Modifiers
Leukotrienes arereleased from mast cells, eosinophils, and other inflammatoryc ells in the airways of patients with asthma. 44 Cysteinyl leukotrienes, C 4 ,D 4 ,a nd E 4 , released primarily from activated eosinophils and mast cells, arep otent contributors to the physiological and pathological changes characteristic of asthma. 45 They areseveral orders of magnitude morepotent than acetylcholine and histamine as contractile agonists of human airways. 45,46 Leukotrienes increase microvascular permeability, modulate the primarya fferent nerve fibers, stimulate mucus release, slow mucus transport, and decrease the activity of human respiratorycilia. 45 Antileukotriene therapies inhibit synthesis of leukotrienes through 5-lipoxygenase (ALOX5) inhibition or by blocking the cysteinyl leukotriene receptor. 46 The -444 leukotriene C4 synthase gene polymorphism (LTC4S) has been correlated with the response of asthma patients to zafirlukast, al eukotriene receptor antagonist. 36 Anderson and colleagues genotyped asthma patients for polymorphisms in the promoter region of ALOX5 and LTC4S. These individuals werep articipating in a randomized, double-blind, parallel study of inhaled fluticasone (88 mcg twice daily) and zafirlukast (20 mg twice daily). Results showed that subject' sh omozygous for mutations in either ALOX5 or LTC4S had ar educed response to zafirlukast therapy.R esults from this same study of 68 patients with mild asthma showed that zafirlukast had no activity in LTC4S C/C homozygotes compared with heterozygotes and carriers of the Aa llele based on percentage change in FEV 1 (-3%, +9%, +9%, respectively). 36 Athirdstudy of 23 patients with chronic, severe asthma indicated ad ifferent relationship between the LTC4 genotype and response to zafirlukast. In this trial, the FEV 1 response to zafirlukast was increased in heterozygotes and C/C homozygotes while A/A homozygotes had ad ecrease in FEV 1 with zafirlukast. 47 The reasons for the different patterns of results arenot clear,although it may be attributed to differences between population types. Among 114 individuals receiving high-dose zafirlukast, 104 wild-type or heterozygous patients had an 18.8% improvement in FEV 1 after 1week of treatment. In contrast, 10 patients with the mutant genotype had no benefit from active treatment, as measured by an average change in FEV 1 of -1.2%. None of the patients with the mutant genotype at the ALOX5 corepromoter locus manifested a>12% improvement in FEV 1 at the end of the treatment period. 48

Glucocorticoids
Glucocorticoids aret he most potent anti-inflammatory drugs used for asthma treatment. 30 They act by binding to an intracellular glucocorticoid receptor (GR) to form ac omplex. The receptor-ligand complex translocates to the nucleus where it regulates gene expression, decreasing transcription of various proinflammatoryp roteins and increasing transcription of anti-inflammatoryp roteins. 30,40 Glucocorticoids also increase transcription of beta 2-adrenoceptors and muscarinic receptors. This increase in transcription may help to shift airway regulation from vagally mediated bronchoconstriction to sympathetically mediated bronchorelaxation. 30 The clinical efficacy of glucocorticoid therapy is derived from acombination of anti-inflammatoryeffects in the lung, reduction of inflammatoryc ell survival, and inhibition of inflammatory cytokine production. 49 Despite their well-known efficacy, therei sas ubset of asthmatic patients who areu nresponsive to corticosteroids. [49][50][51][52] These patients demonstrate persistent respiratorys ymptoms, nocturnal exacerbations, persistent airway obstruction, and inflammation, even though their treatment includes high doses of systemic glucocorticoids. [49][50][51][52] Clinical studies have shown about 5% to10% of all patients with asthma and up to 35% of those with severed isease have reduced responses to glucocorticosteroid therapy. [50][51][52] African Americans may appear to have ar acial predisposition to decreased responsitivity to glucocorticosteroid therapy,w hich was approximately 40% in poorly controlled patients. 52 It has been shown that some glucocorticoid-resistant patients have abnormalities in the activity of proinflammatory transcription factors AP-1 and NF-K B. 30 Both AP-1 and NF-K Ba ct by inducing the transcription of chemoattractants, cytokines, cytokine receptors, and cell adhesion molecules. 40 Many cases of glucocorticoid resistance may be due to mutations or polymorphisms present in the glucocorticoid receptor gene (GR/NR3C1). 37 Atotal of 15 missense, 3nonsense, 3frameshift, 1s plice site, and 2a lternative spliced mutations have been reported in the NR3C1 gene. These mutations have been associated with glucocorticoid resistance. 37 Thereare 2naturally occurring isoforms of the NR3C1: GRα

Implications of Pharmacogenomics in the Current and Future Treatment of Asthma
(functional) and GRβ (no hormone-binding ability). 37 The glucocorticoid-GRα complex can directly or indirectly alter gene transcription by binding to specific DNA sites or through transcription factor activation. GRα may also be involved with down-regulation of proinflammatorym ediators and upregulation of anti-inflammatorym ediators. GRβ is thought to act as an endogenous inhibitor of glucocorticoid action. 37,38,40 Leung and colleagues 38 carried out bronchoalveolar lavage (BAL) in 6steroid-resistant and 6steroid-sensitive patients with asthma beforea nd after 1w eek of treatment with 40 mg/day prednisone. Beforep rednisone therapy,t herew eres ignificantly greater numbers of BAL cells expressing IL (interleukin)-2 mRNA ( P <0.01) and IL-4 mRNA ( P <0.05) in steroid-resistant patients with asthma, as compared with steroid-sensitive patients. 38 There werenobetween-group differences observed in the numbers of BAL cells expressing interferon (IFN)-γ or IL-5 mRNA expression. After 1w eek of prednisone treatment, IL-2 expression was not significantly altered in either group. However,s teroid-sensitive patients had as ignificant decrease in the numbers of BAL cells expressing mRNA for IL-4 ( P <0.01) and IL-5 ( P <0.001), and a rise in the numbers of IFN-γ mRNA+ cells ( P <0.01). In contrast, after prednisone treatment, the patients with steroid resistance had no significant change in either the number of BAL cells expressing mRNA for IL-4 or IL-5. 38 An imbalance in the activity of either isoform due to agenetic anomaly may increase the risk of glucocorticoid resistance. The synthesis of glucocorticoid receptors is strongly influenced by interleukins. Genetic polymorphisms that alter expression of several interleukins have been associated with reduced responsivity to corticosteroids in patients with asthma. 38,40 To date, 2t ypes of steroid-resistant (SR) asthma have been identified: type I( >95% of cases) is cytokine induced and is associated with increased expression of GRβ ,al ess active GR isoform, and type II (<5% of cases) is due to low numbers of GRs. Clinically,T ype IS Ra sthmatic patients present with severes ide effects, including adrenal gland suppression and Cushingoid features. Ty pe II SR asthmatics have ag eneralized primaryc ortisol resistance and do not develop steroid-induced side effects. 49 Other genetic factors may impact response to corticosteroid therapy.C RHR1 is the primaryr eceptor mediating the release of adrenocorticotrophic hormone, which regulates endogenous cortisol levels and genetic variation in CRHR1 that is associated with improved pulmonaryf unction response to inhaled corticosteroids. 41 The mean percentage change in FEV 1 for those homozygous for the minor allele was 13.3% versus 5.5% for those homozygous for the wild-type allele. 41

Other Therapies
Genetic factors may also influence the safety and efficacy of other commonly used asthma treatments. Cytochrome p450 (CYP) 1A2 is involved in the metabolism of theophylline, and a polymorphism for the gene encoding this enzyme, -2964 (G/A), has been correlated with reduced theophylline clearance versus that in patients with the G/G genotype. Thus, theophylline may requirereduced dosing in patients with the Aallele at site -2964 (G/A) in the CYP1A2 gene to avoid possible toxicity. 42 Histamine is abronchoconstrictor involved in the pathogenesis of asthma, and histamine N-methyltransferase plays acentral role in histamine catabolism in bronchial tissue. The T314 allele of the gene for histamine N-methyltransferase results in decreased enzyme activity and possibly also increased bronchoconstriction in patients with asthma. It may be important to use antihistamines that do not, themselves, inhibit this enzyme in asthma patients with the T314 allele. 30 Eotaxin (chemokine, CC motif, ligand; CCL11) is ap otent eosinophil chemoattractant that plays as ignificant role in the pathology of asthma. Recent results have indicated that the genetic variation at the CCL11 locus is an important determinant of serum total IgE levels among patients with asthma, 53 and it is reasonable to suggest that CCL11 genotype may influence the response to medications that exert their effect via IgE receptors. Omalizumab is ar ecombinant anti-IgE antibody therapy for asthma targeted at patients with elevated IgE levels. 54 Thus, in theory, this genotype might predict ap ositive response to omalizumab in asthma patients, but studies carried out, to date, have not evaluated this possibility.
The results presented in this section indicate that therea re numerous genetically influenced pathways that contribute to the wide interpatient variability in response to commonly prescribed asthma therapies. Currently,n ational guidelines do not suggest testing for these variations. These and other undiscovered variations will undoubtedly play as ignificant role in the future of defining the proper therapy for each individual. Additional research is required to morea ccurately predict therapeutic responses based on individual patient genotypes.

■■ Integration of Molecular Diagnostics With Therapeutics Economic Considerations for Pharmacogenomics
Economic considerations need to be considered in the application of pharmacogenomics to clinical therapy.As et of cost-effectiveness criteria has been proposed to determine when pharmacogenomics is appropriate in selection of therapy and can act as ag uide for futurer esearch. These criteria include: (1) disease has asevereoutcome, defined as asignificant impact on the quality of life, or has expensive medical carec osts, or has ah igh mortality; (2) ad rug' sr esponse is currently not monitored or therei sd ifficulty in monitoring the response; (3) thereisastrong association between gene variant and clinically relevant outcomes; (4) ar apid and relatively inexpensive assay is available; and (5) variant allele frequency is relatively high ( Table 2). 55 These criteria could eventually be considered in the drug selection processes utilized by managed health careplans.
The majority of managed health carep lans use prior-authorization (PA) programs to ensurea ppropriate utilization of specified drugs and to reinforce prescription guidelines. As genomic testing advances from aresearch tool to aclinical tool, managed carep lans will be tasked to integrate the testing into the PA process. Adding the above criteria will remind physicians to consider the value of genetic testing when expected therapy outcomes aren ot achieved with optimally applied, comprehensive management regimens using current evidencebased treatment guidelines combined with awell-designed and well-run disease management program. It will also give al evel of confidence that targeted therapies arebeing used in the most appropriate manner.

Current Application of Pharmacogenomics
Genetic and genomic testing and analysis area lready being incorporated into treatment decisions for patients with many diseases. For example, estrogen receptor and progesterone receptor status areu sed to select breast cancer patients likely to respond to hormone therapy. 56 Human epidermal growth factor receptor (HER-2 [c-erbB2/neu]) expression is also used to help guide treatment selection in women with breast cancer, with significant overall survival benefit following chemotherapy in targeted patients. 57 Results from studies of patients with other malignancies demonstrated clear genetic determination of responses to therapy. 58,59 Genotype has also been demonstrated to influence responses to therapy in hepatitis Cp atients. Results from ar ecent study of patients with chronic hepatitis Ci ndicated that increased hepatic expression of suppressor of cytokine signaling (SOCS)-3 mRNA was significantly associated with lack of response to IFN treatment. 60 G enetic polymorphisms that influence responsiveness to antidepressant therapy have also been identified. Although substantial further research is required, in the future, pharmacogenetic approaches may potentially affect the treatment of major depression. 61 Specific genetic variants have also been associated with responses to therapy in patients with schizophrenia. 62 An early yet growing body of evidence shows that incorporating our understanding of genomics into clinical practice can lead to clinical benefit. Genetic predictors of responses to specific therapies could be helpful in patients with asthma and clinicians should be educated regarding these determinants. 63,64 At present, thereh as been little integration of genomics and genetic testing for determination of best approaches to therapy for patients with asthma. However,r esults from several studies might have "set the stage" for this approach. For example, it has been noted that the association of the CRHR1 gene, as well as 1s pecific haplotype within the CRHR1 gene, with the degree of response to inhaled corticosteroids, may provide the basis for afirst step in the development of individualized therapy for asthma. 65 However,the applicability of genomic and genetic testing faces significant challenges. Patients arel ikely to be uncomfortable without the presence of confidentiality safeguards. Physicians will be faced with abewildering array of testing from competing vendors. Managed carec ompanies will face difficulties in tracking and managing the utilization of these complicated tests due to potentially high costs and lack of an adequate coding system for billing. They will also face difficulties in coordinating all of the contracts in arapidly expanding field. Pharmaceutical companies will face situations in which decisions to control utilization of their products arei nfluenced by testing that is likely to be less than 100% sensitive or 100% specific. Patients will be caught in the middle.
It is obvious that standards of carew ill be sorely needed to guide this process. Most importantly,i ti se ssential that future clinical trials demonstrate that the clinical benefits achieved with therapy selected on the basis of pharmacogenetic analysis justify the cost of testing. Ar ecent modeling study carried out by Stallings and colleagues compared the annualized per-patient cost testing all asthma patients for anonresponse genotype prior to treating versus no testing. They estimated that the savings associated with the testing strategy ranged from $200 to $767

■■ Conclusions
We now have moreinformation about the genetic underpinnings of interpatient variability in response to therapies used in patients with asthma. Thereare clear examples of gene polymorphisms that can influence responses to beta 2-agonists, glucocorticosteroids, and leukotriene modifiers. However,itmust be remembered that despite substantial progress, no individual gene polymorphisms have been associated with altered responses to treatment in large numbers of patients, which is critical to obtain prior to fielding gene testing. 67 Emerging results for aw ide range of diseases, including asthma, indicate that standards of careestablished in treatment guidelines may not be uniformly applicable to the entire population of patients with ag iven disease because of multiple causes, one of which is gaining recognition: genetic variation in treatment response. In asthma, thereissignificant genetically determined variation in response to the 3m ain modes of therapy: inhaled corticosteroids, beta 2-agonists, and leukotriene response modifiers. These genetically determined variations in response arei mportant to keep in mind when clinicians make modifications to therapeutic regimens for asthma therapy to achieve control of symptoms and exacerbations. Understanding the impact of genetic variations on response to therapy has the potential to improve care, decrease side effects, and improve patient outcomes.
Managed carep hysicians and patients will soon enter an ew era of complexity that will requires ignificant education. It is important that they understand the therapeutic as well as the social and economic implications of our increased understanding of both the genetics of disease and responses to specific therapies. Thereare important and difficult ethical issues related to genetic testing (e.g., cost insurability,e mployability,m edical prognosis and treatment decisions based on genetic information) that must be addressed by both health careproviders and society in general.

Disclosures
No outside funding supported this research. Author Thomas J. Morrow worked as an independent consultant and had ap rimarya ffiliation with Teva Neuroscience during the time that this article was prepared. After submission of this article, the author joined Genentech as adirector in the Value-Based Health department.